Earlier studies showed that IA-2 and IA-2B are enzymatically inactive members of the protein tyrosine phosphatase family, widely distributed in neuroendocrine cells throughout the body and transmembrane components of DCV. Further studies showed that IA-2/IA-2B belong to an ancient gene family going back 500 million years with homologs in Drosophila and C. elegans. Studies over the last several years, in mice, showed that IA-2 and IA-2B, which influence the secretion of hormones, also modulate the secretion of neurotransmitters in the brain. These observations led to the discovery that the knockout of the IA-2/IA-2B genes result in profound changes in behavior, learning and lifespan. Additional studies revealed that the knockout of IA-2/IA-2B also have a profound effect on the circadian rhythm of blood pressure, heart rate, body temperature and physical activity. These observations point to the possibility that in mice and in humans, alterations in one or more of the many non-circadian structural proteins of secretory vesicles may similarly affect circadian timing and, in turn, a variety of other physiological functions. Over the last year we showed that the knockout of IA-2/IA-2B impairs the secretion of insulin by reducing the number of DCV. This was determined by a variety of techniques including electron and two-photon microscopy, membrane capacitance, Ca2+ currents, DCV half-life, quantifying lysosome number and size and studies on autophagy. Islets from single and DKO mice revealed a significant decrease in insulin content, insulin secretion and the number and half-life of DCV (P <0.05 to 0.001). Exocytosis as evaluated by two-photon microscopy, membrane capacitance and Ca2+ currents supported these findings. Electron microscopy of islets from KO mice revealed a marked increase (P <0.05 to 0.001) in the number and size of lysosomes and enzymatic studies showed an increase in cathepsin D activity (P <0.01). LC3 protein, an indicator of autophagy, also was increased in islets of KO as compared to WT mice (P <0.05 to 0.01) suggesting that autophagy might be involved in the deletion of DCV. We conclude that the decrease in insulin content and secretion, resulting from the deletion of IA-2 and/or IA-2B, is due to a decrease in the number of DCV.